A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients.

MedLine Citation:

PMID:
22850565
Owner:
NLM
Status:
Publisher

Abstract/OtherAbstract:

PURPOSE: Imatinib minimal (trough) plasma concentrations after 1 month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). Considering a retrospective pharmacokinetic (PK) analysis has also suggested that imatinib clearance increases over time in soft tissue sarcoma and GIST patients, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population PK study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib. EXPERIMENTAL DESIGN: Full PK blood sampling was performed in 50 GIST patients on the first day of imatinib treatment, and after 1, 6 and 12 months. Additionally, on day 14, and monthly during imatinib treatment, trough samples were taken. PK analysis was performed using a compartmental model. Volume of liver metastases was assessed by CT imaging. RESULTS: After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared to baseline was observed (P less than 0.01). For every 100 cm3 increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed. CONCLUSIONS: This is the first prospective PK study in GIST patients, demonstrating a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future 'trough level - clinical benefit' analyses should be time-point specific. GIST liver involvement however has a marginal effect on imatinib clearance.